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Background

This common soft tissue tumor is most commonly found in the skin of children and young adults.

OUTLINE

Epidemiology  
Disease Associations  
Pathogenesis  
Laboratory/Radiologic/Other Diagnostic Testing  
Gross Appearance and Clinical Variants  
Histopathological Features and Variants  
Special Stains/
Immunohistochemistry/
Electron Microscopy
 
Differential Diagnosis  
Prognosis  
Treatment  
Commonly Used Terms  
Internet Links  

DISEASE ASSOCIATIONS CHARACTERIZATION
TRIAD OF LEUKEMIA, NEUROFIBROMATOSIS, AND JXG  
Juvenile myelomonocytic leukemia presenting with features of hemophagocytic lymphohistiocytosis in association with neurofibromatosis and juvenile xanthogranulomas.

Shin HT, Harris MB, Orlow SJ.

Ronald O. Perelman Department of Dermatology, New York University School of Medicine, New York, New York 10016, USA.
J Pediatr Hematol Oncol. 2004 Sep;26(9):591-5. Abstract quote  

An association exists among neurofibromatosis 1 (NF1), juvenile xanthogranulomas (JXGs), and juvenile myelomonocytic leukemia (JMML). The authors describe a patient with the triple association of JXG, NF1, and JMML initially presenting with features of hemophagocytic lymphohistiocytosis (HLH).

An 18-month old boy had multiple cutaneous and gastrointestinal JXG and NF1. At 3 years of age he developed anemia, thrombocytopenia, and hepatosplenomegaly.

A bone marrow biopsy revealed features of HLH. Despite chemotherapy, he went on to develop JMML, which proved fatal.
Juvenile xanthogranuloma associated with neurofibromatosis 1: 14 patients without evidence of hematologic malignancies.

Cambiaghi S, Restano L, Caputo R.

Istituto di Scienze Dermatologiche, IRCCS, Ospedale Maggiore e Universita di Milano, Via Pace 9, 20122 Milan, Italy.
Pediatr Dermatol. 2004 Mar-Apr;21(2):97-101. Abstract quote  

The clinical features and natural history of juvenile xanthogranuloma (JXG) in 14 children affected by neurofibromatosis 1 (NF1) are reported. Mean follow-up in 11 of these patients was 4.3 years (range 1-10 years). None of the children developed hematologic malignancies during this period. The onset of JXG was in the first 2 years of life in 13 of the patients.

In this series, the association between JXG and six or more cafe au lait spots more than 5 mm in diameter was a good marker for NF1 in the first few years of life.

Overall the JXG in these patients did not show any features distinguishable from those of "classical" JXG.
Juvenile xanthogranuloma, neurofibromatosis, and juvenile chronic myelogenous leukemia. World statistical analysis.

Zvulunov A, Barak Y, Metzker A.

Dermatology Unit, Children's Medical Center of Israel, Petah Tiqwa.
Arch Dermatol. 1995 Aug;131(8):904-8. Abstract quote  

BACKGROUND AND DESIGN: The concurrent finding of neurofibromatosis type 1 (NF), juvenile chronic myelogenous leukemia (JCML), and juvenile xanthogranuloma (JXG) has been repeatedly reported. Juvenile chronic myelogenous leukemia has been found more frequently in patients with NF and may present with various cutaneous manifestations, including JXG. To our knowledge, the relationship among these three entities has never been explored. The purpose of the present study is to explore this relationship by using a systematic review of the literature. We present five demonstrative cases of various associations among NF, JCML, and JXG.

RESULTS: A family history of NF was found in 85% to 95% of children with NF and JCML (with or without JXG), as compared with that found in 47% of children with NF and JXG. The observed frequency of the triple association is 30-fold to 40-fold higher than that expected. It is estimated that children with NF and JXG have a 20-fold to 32-fold higher risk for JCML than do patients with NF who do not have JXG.

CONCLUSIONS: A concomitant finding of JCML and JXG in children with NF represents a true association, rather than a coincidence. A finding of JXG in an infant with NF should alert a physician to a possible development of JCML.
NEVUS SEBACEUS  

A Case of Juvenile Xanthogranuloma Arising on a Nevus Sebaceus

Sung Eun Chang, M.D.; Jee Ho Choi, M.D.; Kyung Jeh Sung, M.D.; Kee Chan Moon, M.D.; Jai Kyoung Koh, M.D.

From the Department of Dermatology, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, Korea.

Am J Dermatopathol 2001;23:347-350 Abstract quote

Various epithelial and mesenchymal neoplasms can arise in nevus sebaceus (NS). Juvenile xanthogranuloma arising on an NS has not been reported previously. Juvenile xanthogranuloma, a disease characterized by reactive histiocytic proliferation, could be included in the list of secondary alterations arising on an NS.

PANCYTOPENIA  
Prolonged severe pancytopenia preceding the cutaneous lesions of juvenile xanthogranuloma.

Hara T, Ohga S, Hattori S, Hatano M, Kaku N, Nomura A, Takada H, Kokuba H, Ohshima K, Hara T.

Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Pediatr Blood Cancer. 2005 Jul 26; [Epub ahead of print] Abstract quote  

We report a case of juvenile xanthogranuloma (JXG) having progressive pancytopenia for 6 months until the proliferating skin lesions.

A 2-month-old infant presented recurrent fever, anemia, and hepatosplenomegaly mimicking hemophagocytic lymphohistiocytosis (HLH) or juvenile myelomonocytic leukemia (JMML). At 8 months of age, the biopsy of a growing papule on the elbow made the diagnosis. Bone marrow (BM) specimens showed clustering foamy cells including hemophagocytosis by histiocytes. Treatment with etoposide followed by vinblastine plus prednisolone (PSL) therapy improved the disease.

Although JXG is a benign non-Langerhans cell histiocytosis, the multisystem-visceral form should be considered as a potential aggressive disease when associated with BM failure in early infancy.

GROSS APPEARANCE/
CLINICAL VARIANTS
CHARACTERIZATION
GENERAL  


Juvenile xanthogranulomas in the first two decades of life: a clinicopathologic study of 174 cases with cutaneous and extracutaneous manifestations.

Dehner LP.

Am J Surg Pathol 2003 May;27(5):579-93 Abstract quote

Juvenile xanthogranulomas (JXG) is a histiocytic disorder, primarily but not exclusively seen throughout the first two decades of life and principally as a solitary cutaneous lesion.

This study is a retrospective clinical and pathologic review of 174 cases documenting the cutaneous and extracutaneous manifestations in patients presenting from the neonatal period to 20 years of age (mean 3.3 years; median 1 year). There was a male predominance (99 male:75 female) in all categories of clinical presentation, but especially notable in the group with multiple cutaneous lesions (12 male:1 female). A solitary cutaneous lesion accounted for 67% of all cases, followed by a solitary subcutaneous or deep soft tissue mass (28 cases, 16%), multiple cutaneous lesions (13 cases, 7%), a solitary extracutaneous, nonsoft tissue lesion (9 cases, 5%), and multiple cutaneous and visceral-systemic lesions (8 cases, 5%).

The recorded deaths due to disease included two neonates with systemic JXG who developed hepatic failure and thrombocytopenia and at autopsy had giant cell-neonatal hepatitis in addition to JXG in the liver and other visceral sites. A third death in a 3-month-old boy with a retroperitoneal-pelvic JXG occurred after failure to control severe hypercalcemia.

The characteristic Touton giant cell in variable numbers was a consistent feature of the cutaneous lesions; however, these cells were either absent or present in reduced numbers in the various extracutaneous lesions when compared with JXG in the skin. Spindle cells intermingled among the mononuclear cells or forming short fascicles were seen in both cutaneous and extracutaneous lesions. Immunohistochemistry was performed on all extracutaneous lesions, and the constituent cells, regardless of their individual morphologic features, were uniformly positive for vimentin, CD68, and factor XIIIa and negative for S-100 protein and CD1a.

It is widely held that JXG is a proliferative disorder of dendrocytes, possibly dermal dendrocytes; thus, its clinical and pathologic similarities to Langerhans cell histiocytosis are not entirely unexpected in light of the most recently proposed international classification of histiocytic disorders, which includes JXG and Langerhans cell histiocytosis together as "dendritic cell-related" histiocytoses.

BREAST  
Mammary Presentation of Adult-Type "Juvenile" Xanthogranuloma.

Shin SJ, Scamman W, Gopalan A, Rosen PP.

From the *Department of Pathology and Laboratory Medicine, Weill Medical College of Cornell University, New York, NY; daggerDepartment of Pathology, Summerlin Hospital, Las Vegas, NV; and double daggerDepartment of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY.


Am J Surg Pathol. 2005 Jun;29(6):827-831. Abstract quote  

Juvenile xanthogranuloma (JXG) is a benign histiocytic disorder of infants and childhood. Approximately 15% of cases occur in adults. Adult JXG characteristically affect patients in their 20s and 30s; however, about 5% of patients are older than 60 years. Adult JXGs rarely regress spontaneously, and reports of concomitant extracutaneous lesions are rare.

Herein, we report an exceptional case of adult xanthogranuloma in a 74-year-old woman who presented with ipsilateral breast masses and also found to have prior cutaneous lesions. This is the first reported case of cutaneous and extracutaneous adult JXG where the latter manifested in the breast as a spindle cell xanthogranuloma.

Histologically, the lesion was composed predominantly of spindle cells with associated multinucleated giant cells and a chronic inflammatory cell infiltrate. Spindle cells were immunoreactive for various histiocytic markers and negative for cytokeratins, S-100, CD34, factor XIIIa, and CD1a.

In the breast, the morphologic features of JXG evoked several entities in the differential diagnosis, including spindle cell metaplastic carcinoma, inflammatory pseudotumor, fibromatosis, myofibroblastoma, and phyllodes tumor. With the aid of immunohistochemical stains and appropriate clinical history, the correct diagnosis of extracutaneous adult JXG manifesting as a spindle cell xanthogranuloma can be made.
CORNEA  
Juvenile xanthogranuloma of the corneoscleral limbus.

Lim-I-Linn Z, Li L.

Cornea Service, Singapore National Eye Centre, Singapore 168751.
Cornea. 2005 Aug;24(6):745-7. Abstract quote  

PURPOSE: To report an 11-year-old Chinese girl with juvenile xanthogranuloma of the limbus, occurring in isolation without dermatologic involvement, and to discuss the clinical and histologic features, pathogenesis, and treatment of juvenile xanthogranuloma.

METHODS: Case report and review of medical literature.

RESULTS: A total excision and biopsy of the limbal lesion with lamellar graft was performed. Histologic examination showed a xanthogranuloma. At 12-month follow-up, there was no recurrence of tumor.

CONCLUSION: The diagnosis of juvenile xanthogranuloma may be straightforward in cases that have concomitant cutaneous manifestations. However, in isolated ocular forms, histopathological examination is necessary. Unlike the more common iris lesions that are preferably treated nonsurgically, limbal lesions require surgical excision.
Juvenile xanthogranuloma of the corneoscleral limbus: case report and review of the literature.

Chaudhry IA, Al-Jishi Z, Shamsi FA, Riley F.

Oculoplastic and Orbit Division, King Khaled Eye Specialist Hospital, PO Box 7191, Riyadh, 11462, Saudi Arabia.

Surv Ophthalmol. 2004 Nov-Dec;49(6):608-14. Abstract quote  

Juvenile xanthogranuloma is a benign histiocytic cutaneous disorder mainly occurring in infants which may affect the eye. Ocular manifestations usually present in the form of iris lesions with secondary hyphema and glaucoma, but juvenile xanthogranuloma may also present as a corneoscleral limbal mass.

We present the case of an 18-month-old female infant with ocular juvenile xanthogranuloma occurring as a corneoscleral limbal mass without associated cutaneous or systemic findings. The limbal mass lesion was excised by lamellar dissection and histopathological studies revealed histiocytes admixed with lymphocytes, plasma cells, and eosinophils; foreign body and Touton giant cells present throughout the specimen confirmed the diagnosis of juvenile xanthogranuloma. At 14-month follow-up, there was no recurrence of the limbal mass. The natural history of this uncommon ocular condition is discussed and the relevant literature reviewed.

Juvenile xanthogranuloma should be considered in the differential diagnosis of any corneoscleral limbal mass lesion, particularly in children.

HISTOLOGICAL TYPES CHARACTERIZATION
General

Proliferation of fibrohistiocytic cells showing mild variation in size and shape
Situated within the dermis and closely abutting against the overlying epidermis
Epidermis may form collarette around proliferation

Cells have clear to amphophilic staining cytoplasm, occasionally vacuolated
No pigment observed unless prior hemorrhage
Rare mitoses
Admixed inflammatory cells including eosinophils
Touton type giant cells occasionally

VARIANTS  
DEEP  

Deep juvenile xanthogranuloma: an unusual presentation.

Neveling U, Kahn LB, Valderrama E, Poustchi-Amin M, Uckan D, Shende A.

Department of Pathology, Long Island Jewish Medical Center, New Hyde Park, NY 11040, USA.

Pediatr Pathol Lab Med 1997 May-Jun;17(3):503-11 Abstract quote

Juvenile xanthogranuloma (JXG) is a disorder of histiocytes usually associated with cutaneous lesions. It may present a diagnostic dilemma in the absence of cutaneous lesions and when deeply located. Differentiation of JXG from other childhood histiocytosis syndromes, especially Langerhans' cell histiocytosis (LCH), is important.

We describe an unusual case of deep JXG in a 27-month-old girl with multiple omental and peritoneal nodules presenting with ascites. Although a diagnosis of LCH was suspected clinically, the absence of Birbeck granules and S-100 protein and T6 antigen negativity, together with CD68 and factor XIIIa positivity, led us to a diagnosis of JXG.

Physicians should be aware of the widening spectrum of manifestations of juvenile xanthogranuloma.

MITOTICALLY ACTIVE  


Mitotically active juvenile xanthogranuloma.

Miguelez A, Rodriguez-Peralto JL, Santos-Briz A, Vargas J, Lopez-Rios F.

Departments of Dermatology (Dr Miguelez) and Pathology (Drs Rodriguez-Peralto, Santos-Briz, Vargas, and Lopez-Rios), 12 de Octubre University Hospital, Madrid, Spain.

Arch Pathol Lab Med 2002 Oct;126(10):1219-21 Abstract quote

Juvenile xanthogranuloma is a histiocytic inflammatory disorder capable of presenting different histologic patterns. The classic form consists of sheets of foamy histiocytes and numerous multinucleated Touton-type giant cells containing no to very few mitotic figures. Nonlipidized juvenile xanthogranuloma consists of a diffuse monomorphic histiocytic infiltrate and usually shows a slightly higher mitotic index. Histologic hematoxylin-eosin staining techniques were used after excision of a pink ulcerated nodule in a 2-year-old girl.

Histopathologic examination showed a nonencapsulated cellular proliferation mainly occupying dermis, but extending into the subcutaneous tissue as well. Most of the cells were epithelioid histiocytes, but foamy and Touton giant cells were also evident. The most striking feature was the presence of a high number of mitotic figures, as many as 23 per 10 high-power fields.

We present an unusual case of classic juvenile xanthogranuloma with areas similar to those found in the nonlipidized type and with a high mitotic index.

 

SPECIAL STAINS/
IMMUNOPEROXIDASE
CHARACTERIZATION
Immunoperoxidase  

``Juvenile'' Xanthogranuloma An Immunophenotypic Study With A Reappraisal of Histogenesis

Madeleine D. Kraus, etal.

Am J Dermatopathol 2001;23:104-111

The non-Langerhans histiocytoses, a nosologic category to which juvenile xanthogranuoma (JXG) belongs, represent a heterogenous collection of disorders related to the monocyte/macrophage lineage. The dermal dendrocyte was previously proposed as the cell of origin for JXG on the basis of Factor XIIIa reactivity, a suggestion that does not fully explain the occasional xanthogranulomatous proliferations localizing exclusively to extracutaneous sites.

This study applies a panel of recently developed immunohistochemical markers to JXGs and relates the phenotype of this process to new concepts of monocyte/dendritic cell ontogeny.

Twenty-seven JXG, ten dermatofibromas (DF), and ten age-matched normal skin specimens were stained using standard immunohistochemistry methods, and all JXGs were fascin+ and CD68+, although 26 of 27 were reactive for HLA-DR, 25 of 27 for Factor XIIIa, 25 of 27 for LCA, 21of 27 for CD4, and 8 of 27 for polyclonal s100. Six of those eight polyclonal S100+ cases were also reactive for monoclonal S100. None of those cases was reactive for CD1a, CD3, CD21, CD34, or CD35. Eight of ten dermatofibromas were FXIIIa+; all were negative for HLA-DR, LCA, CD4, and polyclonal s100. In controls, fascin+ dendritic cells were present but did not stain for Factor XIIIa, S100, or CD4.

Based on the morphologic and phenotypic overlap of the lesional cells in JXGs and plasmacytoid monocytes, it would appear that the plasmacytoid monocyte might be considered the putative normal counterpart of the major cellular population of JXGs, a proposal that helps explain the extra-cutaneous, visceral, and soft tissue location that have been reported for occasional cases of JXG. We would also conclude that neither Factor XIIIa-nor S100+ results should preclude the diagnosis of JXG, and find that reactivity for CD4 and LCA may be used to distinguish JXG from DF when the latter is heavily lipidized or the former is not.

 

DIFFERENTIAL DIAGNOSIS CHARACTERIZATION

Xanthogranulomas With Inconspicuous Foam Cells and Giant Cells Mimicking Malignant Melanoma A Clinical, Histologic, and Immunohistochemical Study of Three Cases

Klaus J. Busam, M.D.; Juan Rosai, M.D.; Kristin Iversen, B.S.; Achim A. Jungbluth, M.D.

From the Department of Pathology (K.J.B., J.R.), Memorial Sloan-Kettering Cancer Center; and the Ludwig Institute for Cancer Research (K.I., A.A.J.), New York Branch, New York, NY, U.S.A.

Am J Surg Pathol 2000;24:864-869 Abstract quote

Histiocytic proliferations can mimic melanocytic tumors and vice versa. The authors describe the clinical, histologic, and immunohistochemical findings of three predominantly mononuclear xanthogranulomas that were misdiagnosed as malignant melanoma by experienced pathologists.

All lesions occurred in male patients ranging in age from 14 to 75 years. The tumors presented as dermal nodules, two of which were surrounded by an epidermal collarette and were ulcerated focally. The tumors were composed of a mixed population of large epithelioid and plump spindle cells with pink or pale cytoplasm arranged in nests and short fascicles. Occasional mononuclear cells had cytoplasmic vacuolar changes, but none had well-developed foamy cytoplasm. Rare, multinucleated giant cells were present, but they were not of the Touton type. Mitotic figures were found in all lesions.

Immunohistochemically, most tumor cells (80%90%) were strongly positive for CD68 and a minority of cells (10%15%), located typically at the periphery of the tumor, was positive for factor XIIIa. Two tumors contained rare cells positive for S-100 protein (5% of tumor cells or less). All tumors were completely negative for tyrosinase (T311), gp100 (HMB-45), and Melan-A (A103).

Giant and foam cell-poor variants of juvenile xanthogranuloma have been reported previously, mainly in young children. Their occurrence in adolescents and adults is underrecognized. Knowledge of this variant is important to avoid misdiagnosing a benign tumor as malignant melanoma.

BENIGN CEPHALIC HISTIOCYTOSIS  
Is disseminated juvenile xanthogranulomatosis benign cephalic histiocytosis?

Sidwell RU, Francis N, Slater DN, Mayou SC.

Department of Dermatology, Chelsea and Westminster Hospital, Fulham Road, London SW10 9NH, UK.
Pediatr Dermatol. 2005 Jan-Feb;22(1):40-3. Abstract quote  


We describe an infant with a congenital form of non-Langerhans cell histiocytosis with clinical and pathologic features of both disseminated juvenile xanthogranulomatosis and benign cephalic histiocytosis.

The findings in this case support the concept of these non-Langerhans cell histiocytoses forming part of a spectrum of disease rather than being separate pathologic entities.
ERDHEIM-CHESTER DISEASE  
Erdheim-Chester disease in a child presenting with multiple jaw lesions.

Nagatsuka H, Han PP, Taguchi K, Tsujigiwa H, Gunduz M, Fukunaga J, Sugahara T, Asaumi J, Nagai N.

Department of Oral Pathology and Medicine, Graduate School of Medicine and Dentistry, Okayama University, Okayama, Japan.
J Oral Pathol Med. 2005 Aug;34(7):420-2. Abstract quote  

BACKGROUND: Erdheim-Chester disease is a rare histiocytic disease entity related to juvenile xanthogranuloma. It is a systemic condition, usually occurs in adult, characterized by infiltration of foamy histiocytes within the bone and soft tissues.

METHODS AND RESULTS: We report a case of 13-year-old female patient who first presented with multiple osteolytic lesions of the jaws followed by bilateral symmetrical bone lesions affecting the lower extremities, as well as brain and abdominal involvement. Histological findings of the jaw lesions showed lipid-storing CD68 (+), CD1a (-) histiocytes with Touton type giant cells.

CONCLUSION: To the best of our knowledge, this is the first case of Erdheim-Chester disease with jaw bone lesions occurring as initial presenting symptom.

PROGNOSIS AND TREATMENT CHARACTERIZATION
Juvenile xanthogranuloma in childhood and adolescence: a clinicopathologic study of 129 patients from the kiel pediatric tumor registry.

Janssen D, Harms D.

From the Department of Pediatric Pathology, University of Kiel, Kiel, Germany.
Am J Surg Pathol. 2005 Jan;29(1):21-8. Abstract quote  

Juvenile xanthogranuloma (JXG) is an uncommon non-Langerhans cell histiocytosis. We investigated 148 biopsy specimens from 129 patients collected in the Kiel Pediatric Tumor Registry (KPTR) between 1965 and 2001. The clinical, histologic, and immunohistochemical characteristics of JXG were evaluated to gain more and deeper insights into the morphology and clinical behavior of JXG.

Conventionally stained lesions were classified into the following morphologic subtypes: early JXG (EJXG), classic JXG (CJXG), transitional JXG (TJXG), or combined lesions with more than one basic pattern (combined JXG). Immunohistochemistry included antibodies against macrophages (Ki-M1P), S-100 protein, CD1a, and factor XIIIa (FXIIIa).

Clinical data were obtained by means of a standardized questionnaire. The relative incidence of JXG in the KPTR is 0.52%. The male/female ratio was 1.4:1. The mean age was 22.4 months (median, 5 months; range, 0-244 months). A total of 34.5% of the cases of JXG were congenital, and 71.0% of the lesions were diagnosed within the first year of life. Most cases of cutaneous JXG were solitary (81.0%). Five cases (3.9%) presented with visceral (systemic) involvement. Histologically, CJXG was most frequent (47.2%), followed by EJXG (27.1%) and TJXG (16.0%). A total of 9.7% of the lesions represented combined JXG. Histiocytes, including giant cells, were positive for Ki-M1P (100%) and in most cases for FXIIIa (99%). The CD1a and S-100 protein reactions were generally negative.

Clinical and follow-up data showed a generally favorable prognosis with a low relapse rate (7.0%) and even complete involution after incomplete resection. Only 1 of 5 patients with widespread congenital systemic disease died after 34 days. JXG is an uncommon, mostly cutaneous, and prognostically favorable histiocytic tumor of infancy.

Simple tumor excision is the therapy for choice except in the very rare systemic JXG, in which multimodal chemotherapy is indicated.
TREATMENT  

Henry JB. Clinical Diagnosis and Management by Laboratory Methods. Twentieth Edition. WB Saunders. 2001.
Rosai J. Ackerman's Surgical Pathology. Ninth Edition. Mosby 2004.
Sternberg S. Diagnostic Surgical Pathology. Fourth Edition. Lipincott Williams and Wilkins 2004.
Robbins Pathologic Basis of Disease. Seventh Edition. WB Saunders 2005.
DeMay RM. The Art and Science of Cytopathology. Volume 1 and 2. ASCP Press. 1996.
Weedon D. Weedon's Skin Pathology Second Edition. Churchill Livingstone. 2002
Fitzpatrick's Dermatology in General Medicine. 5th Edition. McGraw-Hill. 1999.
Weiss SW and Goldblum JR. Enzinger and Weiss's Soft Tissue Tumors. Fourth Edition. Mosby 2001.


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Last Updated August 16, 2005

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